WO2023192534A1 - Agents de dégradation de kinase 9 dépendante des cyclines (cdk9) et procédés d'utilisation associés - Google Patents

Agents de dégradation de kinase 9 dépendante des cyclines (cdk9) et procédés d'utilisation associés Download PDF

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WO2023192534A1
WO2023192534A1 PCT/US2023/016989 US2023016989W WO2023192534A1 WO 2023192534 A1 WO2023192534 A1 WO 2023192534A1 US 2023016989 W US2023016989 W US 2023016989W WO 2023192534 A1 WO2023192534 A1 WO 2023192534A1
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compound
carcinoma
cancer
moiety
ligand
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Oluwatosin R. AYINDE
James R. Fuchs
John Byrd
Chia SHARPE
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Ohio State Innovation Foundation
University Of Cincinnati
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/545—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • CDK9 Cyclin-Dependent Kinase 9
  • PROTACs proteolysis targeting chimeras; e.g., see U.S. Patent Application Publication No. 2016/0058872, published March 3, 2016
  • PROTACs are heterobifunctional molecules containing two small molecule binding moi eties, joined together by a linker.
  • One of the small molecule ligands is designed to bind with high affinity to a target protein in the cell while the other ligand is able to bind with high affinity to an E3 ligase.
  • the PROTAC selectively binds to the target protein of interest.
  • the PROTAC then recruits a specific E3 ligase to the target protein to form a ternary' complex with both the target protein and the E3 ligase held in close proximity.
  • the E3 ligase then recruits an E2 conjugating enzyme to the ternary complex.
  • the E2 is then able to ubiquitinate the target protein, labelling an available lysine residue on the protein, and then the E2 dissociates from the ternary complex.
  • the E3 ligase can then recruit additional E2 molecules resulting in poly-ubiquitination of the target protein, labelling the target protein for degradation by the cell’s proteasome machinery.
  • the PROTAC can then dissociate from the target protein and initiate another catalytic cycle.
  • the poly-ubiquitinated target protein is recognized and degraded by the proteasome.
  • CDK9 serine/threonine kinase cyclin-dependent kinase 9
  • CDK9 and its regulatory cyclin "IT assemble the functional positive transcription elongation factor b (P-TEFb) complex, which phosphorylates the C-terminal domain (CTD) of the largest domain of the multiprotein complex RNA polymerase 11 (Pol II) RPB 1/POLR2A.
  • CTD C-terminal domain
  • Pol II transitions from abortive to productive elongation. Therefore, CDK9 is heavily involved in the regulation of transcription.
  • Other CDK9/cyclin Tl phosphorylation targets include EP300, MYODI, RPB1/POLR2 A, and .AR as well as the negative elongation factors DSIF and NELF.
  • CDK9 Due to its central role transcriptional regulation, which is frequently dysreguiated in cancer, CDK9 has become the target of several drug development efforts. Dysregulation of CDK9 has been observed in a number of solid tumors, including prostate cancer, neuroblastoma, hepatocellular carcinoma, and lymphoma. Moreover, osteosarcoma patients with high CDK9 tumor-expression levels have significantly shorter survival than patients with low CDK9 expression. CDK9 pathway dysregulation has likewise been observed in liquid tumors, such as acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Even though several CDK9 inhibitors are available, CDK9 is difficult to therapeutically inhibit with small molecules since the structure of its catalytic ATP-binding cleft is similar to many other kinases. Therefore, selective inhibition of CDK9 is challenging.
  • AML acute myeloid leukemia
  • ALL acute lymphoblastic leukemia
  • CDK9 degraders that include a CDK9 binding moiety, such as AT7519 or VIP 152, conjugated to a E.3 ubiquitin ligase binding moiety, such as thalidomide, lenalidomide, or pomalidomide. These degraders can induce the ubiquitination of CDK9 and promote its degradation in cells.
  • the linker covalently tethering the CDK9 binding moiety to the E3 ubiquitin ligase binding moiety can be selected to tune the solubility profile and potency of the degrader. Accordingly, the present disclosure provides compounds, compositions, kits, uses, and methods for the treatment of cancer (e.g., blood cancers such as acute myeloid leukemia or acute lymphoblastic leukemia).
  • cancer e.g., blood cancers such as acute myeloid leukemia or acute lymphoblastic leukemia.
  • CDK9 degraders defined by Formula I
  • L comprises one or more linking groups selected from optionally substituted -Cl 10 alkylene-, -O-C1-10 alkylene-, -C1- 10 alkenylene-, -O-C1-10 alkenylene-, -C1- 10 alkynylene-, -O-C1-10 alkynylene-, -arylene-, -heteroarylene-, -cycloalkylene-, - heterocycloalkylene-, -O-, -S-, -S-S-, -S(O) W -, -C(O)-, -C(O)O-, -OC(O)-, -C(O)S-> - SC(O)-, -OC(O)O-, -N(R b )-, -C(O)N(R b )-, -N(R b )C(O)-, -OC(O)N(R b )-,
  • E comprises an E3 ubiquitin ligase ligand moiety.
  • L comprises one or more linking groups selected from optionally substituted -Cl alkylene-, -O-C1-10 alkylene-, -C1-10 alkenylene-, -O-C1-10 alkenylene-, -C1-10 alkynylene-, -O-C1-10 alkynylene-, -arylene-, -heteroarylene-, -cycloalkylene-, - heterocycloalkylene-, -O-, -S-, -S-S-, -S(O) w -, -C(O)-, -C(O)O-, -OC(O)-, -C(O)S-, - SC(O)-, -OC(O)O-, -N(R b )-, -C(O)N(R b )-, -N(R b )C(O)-, -OC(O)N(R b >, -N
  • E comprises an E3 ubiquitin ligase ligand moiety.
  • L comprises one or more linking groups independently selected from optionally substituted -C1-10 alkynylene-, -O-C1-10 alkynylene-, -arylene-, -heteroarylene-, -cycloalkylene-, and -heterocycloalkylene-.
  • L comprises at least two linking groups independently selected from optionally substituted -C1-10 alkynylene-, - heteroarylene-, and -heterocycloalkylene-
  • L comprises at least two heterocycl oalkylene groups.
  • L comprises at least one piperidine moiety
  • L comprises at least one piperazine moiety.
  • L comprises at least one triazole moiety, such as a 1,2,3 -triazole moiety.
  • L comprises at least one alkynyl moiety.
  • L comprises at least one azetidine moiety.
  • L comprises at least two moieties independently selected from a piperidine moiety, a piperazine moiety, a triazole moiety, such as a 1,2, 3 -triazole moiety, an alkynyl moiety, and an azetidine moiety.
  • L comprises a piperidine moiety
  • L further comprises at least one additional linking group selected from optionally substituted -C1-10 alkynylene-, -O-C1-10 alkynylene-, -arylene-, -heteroarylene-, - cycloalkylene-, and - heterocycloalkylene.
  • L has a length of at least 8 atoms or at least 10 atoms, such as a length of from 8 atoms to 25 atoms, from 10 atoms to 25 atoms, from 8 atoms to 20 atoms, or from 10 atoms to 20 atoms
  • L is not defined by the structure below
  • compositions comprising one or more of CDK9 degraders described herein, or a pharmaceutically acceptable salt thereof, and a physiologically compatible carrier medium.
  • the cancer is a solid tumor or a hematological cancer.
  • the cancer is a leukemia or a lymphoma
  • the cancer is acute myeloid leukemia or acute lymphoblastic leukemia.
  • CDK9 degrader described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a CDK9 degrader described herein, to the subject.
  • the E3 ubiquitin ligase is Cereblon or von Hippel-Findau tumor suppressor (VHF).
  • kits comprising a CDK9 degrader described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a CDK9 degrader described herein.
  • the kit further comprises instructions for administration (e.g ., human administration) and/or use. DESCRIPTION OF DRAWINGS
  • Figure 1 Western blots showing CDK9 degradation (of both 42 kDa and 55kDa isoforms) and MCL-1 downstream repression by triazole-containing PROTACs in MV411 cells after 6-hour drugging.
  • FIGS 2A-2B Correlation coefficients and graphical representations of curve fit for triazole-containing PROTACs (except compounds 4.7b and 4.9c) between both LogD and logk’80 (10X) and -Log( ⁇ M IC?o) (-1 * Logio ( ⁇ M ICsos in MV411 cells ( Figure 2A) and -LogQiM DCso) (-1* Logio ( ⁇ M DCsos in MV411 cells ( Figure 2B).
  • Figures 3A-3C In vitro cellular potency (against MV411 cells) in human serum (HS) versus fetal bovine serum (FBS) for compounds 4.7b (Figure 3A) 4.9c ( Figure 3B), and 4.8a ( Figure 3C).
  • FIGS 4A-4B Graphical plot of cytotoxicity (ICso) against lipophilicity (logk’80) for the AT7519 click series ( Figure 4A) and the VIP152-based degrader series ( Figure 4B).
  • Figure 5 Graphical plot of kinetic solubility against lipophilicity (10*logk’80) for VIP152-based degraders indicating degraders with above or below average KS and/or lipophilicity.
  • Figure 6 Graphical plot of cytotoxicity (ICso) against kinetic solubility (logS) for VIP152-based degraders indicating compounds with above or below average KS and/or in vitro potency.
  • Figure 7 Graph of cellular cytotoxicity of all AT7519-inspired triazole containing degraders against predicted and chromatographic logD.
  • bifunctional compounds that bind CDK9 and recruit an E3 ligase (e.g., Cereblon, VHL) to promote the degradation of CDK9.
  • the disclosure provides compounds of Formula I, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof.
  • the disclosure provides compounds of Formula II, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and pharmaceutical compositions thereof.
  • the compounds are useful for the treatment of diseases associated with CDK9 (e.g., cancer) in a subject in need thereof. Definitions
  • n-membered where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n.
  • piperidinyl is an example of a 6-membered heterocycloalkyl ring
  • pyrazolyl is an example of a 5-membered heteroaryl ring
  • pyridyl is an example of a 6-membered heteroaryl ring
  • 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.
  • the phrase “optionally substituted” means unsubstituted or substituted.
  • substituted means that a hydrogen atom is removed and replaced by a substituent. It is to be understood that substitution at a given atom is limited by valency.
  • C n-m indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C 1-4 , C 1-6 , and the like.
  • C n-m alkyl refers to a saturated hydrocarbon group that may be straight-chain or branched, having n to m carbons.
  • alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, //-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-l -butyl, n-pentyl, 3-pentyl, w-hexyl, 1,2,2- trimethylpropyl, and the like.
  • the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms.
  • C n-m alkenyl refers to an alkyl group having one or more double carbon-carbon bonds and having n to m carbons.
  • Example alkenyl groups include, but are not limited to, ethenyl, w-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.
  • the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.
  • C n-m alkynyl refers to an alkyl group having one or more triple carbon-carbon bonds and having n to m carbons.
  • Example alkynyl groups include, but are not limited to, ethynyl, propyn-l-yl, propyn-2-yl, and the like.
  • the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.
  • C n-m alkoxy refers to a group of formula -O-alkyl, wherein the alkyl group has n to m carbons.
  • Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., w-propoxy and isopropoxy), ZerCbutoxy, and the like.
  • the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • C n-m alkylamino refers to a group of formula -NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • C n-m alkoxycarbonyl refers to a group of formula -C(O)O-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • C n-m alkylcarbonyl refers to a group of formula -C(O)- alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms
  • C n-m alkylcarbonylamino refers to a group of formula -NHC(O)-alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • C n-m alkylsulfonylamino refers to a group of formula -NHS(O) 2 -alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • aminosulfonyl refers to a group of formula -S(0)2NH?
  • C n-m alkylaminosulfonyl refers to a group of formula -S(O) 2 NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • di(C n-m alkyl)ami nosulfonyl refers to a group of formula -S(O) 2 N(alkyl)2, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • aminosulfonylamino refers to a group of formula - NHS(O) 2 NH 2 .
  • C n-m alkylaminosulfonylamino refers to a group of formula -NHS(O) 2 NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • di(C n-m alkyl)aminosulfony1 amino refers to a group of formula -NHS(O) 2 N(alkyl)2, wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • aminocarbonylamino employed alone or in combination with other terms, refers to a group of formula -NHC(O)NH 2 .
  • CM alkylaminocarbonyl amino refers to a group of formula -NHC(O)NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • di(C n-m alkyl)aminocarbonylamino refers to a group of formula -NHC(O)N(alkyl) 2 , wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • C n-m alkylcarbamyl refers to a group of formula -C(O)- NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • thio refers to a group of formula -SH.
  • C n-m alkylsulfinyl refers to a group of formula -S(O)- alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • C n-m . alkylsulfonyl refers to a group of formula -S(O) 2 - alkyl, wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • amino refers to a group of formula -NH 2 .
  • aryl employed alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings).
  • C n-m and refers to an and group having from n to m ring carbon atoms.
  • Aryl groups include, e.g., phenyl, naphthyl, antihracenyl, phenanthrenyl, indanyl, indenyl, and the like.
  • aryl groups have from 6 to about 20 carbon atoms, from 6 to about 15 carbon atoms, or from 6 to about 10 carbon atoms.
  • the and group is a substituted or unsubstituted phenyl.
  • carbonyl employed alone or in combination with other terms, refers to a -C(::::O) ⁇ group, which may also be written as C(O).
  • di(C n-m -alkyl)amino refers to a group of formula -N(alkyl)2, wherein the two alkyl groups each has, independently, n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • di(C n-m -alkyl)carbamyl refers to a group of formula - C(O)N(alkyl)2, wherein the two alkyl groups each has, independently, n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • halo refers to F, Cl, Br, or I. In some embodiments, a halo is F, Cl, or Br. In some embodiments, a halo is F or Cl.
  • C n-m haloalkoxy refers to a group of formula -O-haloalkyl having n to m carbon atoms.
  • An example haloalkoxy group is OCF3.
  • the haloalkoxy group is fluorinated only.
  • the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • C n-m haloalkyl refers to an alkyl group having from one halogen atom to 2s+l halogen atoms which may be the same or different, where “s” is the number of carbon atoms in the alkyl group, wherein the alkyl group has n to m carbon atoms.
  • the haloalkyl group is fluorinated only.
  • the alkyl group has I to 6, 1 to
  • cycloalkyl refers to non-aromatic cyclic hydrocarbons including cyclized alkyl and/or alkenyl groups.
  • Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles. Cycloalkyl groups can have 3, 4,
  • Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo or sulfido (e.g., C(O) or C(S)).
  • Cycloalkyl groups also include cycloalkylidenes.
  • Example cycloalkyl groups include cyclopropyl. cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbomyl, norpinyl, norcarnyl, and the like.
  • cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, or adamantyl.
  • the cycloalkyl has 6-10 ring-forming carbon atoms.
  • cycloalkyl is adamantyl.
  • moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring for example, benzo or thienyl derivatives of cyclopentane, cyclohexane, and the like.
  • a cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring.
  • heteroaryl refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen.
  • the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • any ring-forming N in a heteroaryl moiety can be an N-oxide.
  • the hetcroaryl has 5-10 ring atoms and 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • the heteroaryl is a five-membered or six- membereted heteroaryl ring
  • a five-membered heteroaryl ring is a heteroaryl with a ring having five ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S.
  • Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4- oxadiazolyl, 1,3,4-triazoiyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyI.
  • a six-membered heteroaryl ring is a heteroaryl with a ring having six ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S.
  • Exemplary sixmembered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.
  • heterocycloalkyl refers to non-aromatic monocyclic or polycyclic heterocycles having one or more ring-forming heteroatoms selected from O, N, or S. Included in heterocycloalkyl are monocyclic 4-, 5-, 6-, and 7-membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocycles.
  • Example heterocycloalkyl groups include pyrrolidin-2-one, l,3-isoxazolidin-2-one, pyranyl, tetrahydropuran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrroiidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, and the like.
  • Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by oxo or sulfido (e.g., C(O), S(O), C(S), or S(O)a, etc.).
  • the heterocycloalkyl .group can be attached through a ring-forming carbon atom or a ring-forming heteroatom.
  • the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds.
  • heterocycloalkyl moi eties that have one or more aromatic rings fused (/. ⁇ ?., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc.
  • a heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring.
  • the heterocycloalkyl has 4-10, 4-7 or 4-6 ring atoms with 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members.
  • the suffix “-ene” is used to describe a bivalent group with two radical points for forming two covalent bonds with two other moieties.
  • any of the terms as defined above can be modified with the suffix “-ene” to describe a bivalent version of that moiety.
  • a bivalent aiyl ring structure is “arylene,” a bivalent benzene ring structure is “phenylene,” a bivalent heteroaryl ring structure is “heteroarylene,” a bivalent cycloalkyl ring structure is a “cycloalkylene,” a bivalent heterocycloalkyl ring structure is “heterocycloalkylene,” a bivalent cycloalkenyl ring structure is “cycloalkenylene,” a bivalent alkenyl chain is “alkenylene,” and a bivalent alkynyl chain is “alkynylene.”
  • C n-m alkylene refers to a divalent alkyl linking group having n to m carbons.
  • alkylene groups include, but are not limited to, ethan-l,2-diyl, propan-1, 3-diyl, propan-1, 2- diyl, butan-l,4-diyl, butan-1, 3-diyl, butan-I,2-diyl, 2-m ethyl -propan- 1,3 -diyl, and the like.
  • the alkylene moiety contains 2 to 6, 2 to 4, 2 to 3, 1 to 6, 1 to 4, or I to 2 carbon atoms.
  • the definitions or embodiments refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member provided that, the valency of the atom is not exceeded. For example, an azetidine ring may be attached at any position of the ring, whereas a pyridin-3-yl ring is attached at the 3 -position.
  • Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton.
  • Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Example prototropic tautomers include ketone -- enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • the compounds described herein can contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, enantiomerically enriched mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures (e.g., including (/?)- and (5’)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, (-r) (dextrorotatory) forms, (-) (levorotatory) forms, the racemic mixtures thereof, and other mixtures thereof).
  • Additional asymmetric carbon atoms can be present in a substituent, such as an alkyl group.
  • Optical isomers can be obtained in pure form by standard procedures known to those skilled in the art, and include, but are not limited to, diastereomeric salt formation, kinetic resolution, and asymmetric synthesis. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw- Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L.
  • compounds provided herein can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. Unless otherwise stated, when an atom is designated as an isotope or radioisotope (e.g., deuterium, [ 11 C], [ 18 F]), the atom is understood to comprise the isotope or radioisotope in an amount at least greater than the natural abundance of the isotope or radioisotope.
  • isotope or radioisotope e.g., deuterium, [ 11 C], [ 18 F]
  • an atom is designated as “D” or “deuterium”, the position is understood to have deuterium at an abundance that is at least 3000 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 45% incorporation of deuterium).
  • All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g. hydrates and solvates) or can be isolated.
  • preparation of compounds can involve the addition of acids or bases to affect, for example, catalysis of a desired reaction or formation of salt forms such as acid addition salts.
  • Example acids can be inorganic or organic acids and include, but are not limited to, strong and weak acids.
  • Some example acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, 4-nitrobenzoic acid, methanesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, and nitric acid.
  • Some weak acids include, but are not limited to acetic acid, propionic acid, butanoic acid, benzoic acid, tartaric acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, and decanoic acid.
  • Example bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, and sodium bicarbonate.
  • Some example strong bases include, but are not limited to, hydroxide, alkoxides, metal amides, metal hydrides, metal dialkylamides and arylamines, wherein; alkoxides include lithium, sodium and potassium salts of methyl, ethyl and t-butyl oxides; metal amides include sodium amide, potassium amide and lithium amide; metal hydrides include sodium hydride, potassium hydride and lithium hydride; and metal dialkylamides include lithium, sodium, and potassium salts of methyl, ethyl, n-propyl, zso-propyl, n-butyl, rerAbutyl, trimethyl silyl and cyclohexyl substituted amides.
  • the compounds provided herein, or salts thereof are substantially isolated.
  • substantially isolated is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected.
  • Partial separation can include, for example, a composition enriched in the compounds provided herein.
  • Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds provided herein, or salt thereof. Methods for isolating compounds and their salts are routine in the art.
  • ambient temperature and “room temperature” or “it” as used herein, are understood in the art, and refer generally to a temperature, e.g. a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20 °C to about 30 °C.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the present application also includes pharmaceutically acceptable salts of the compounds described herein.
  • “'pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present application include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present application can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (MeCN) are preferred.
  • non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (MeCN) are preferred.
  • suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977). Conventional methods for preparing salt forms are described, for example, in Handbook of Pharmaceutical Salts
  • prodrug refers to a compound that have cleavable groups and become bysolvolysis or under physiological conditions the compounds described herein, which are pharmaceutically active in vivo.
  • Such examples include, but are not limited to, choline ester derivatives and the like, N -alkylmorpholine esters and the like.
  • Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H , Design of Prodrugs, pp. 7- 9, 21-24, Elsevier, Amsterdam 1985).
  • Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides.
  • Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodmgs.
  • double ester type prodmgs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C7-12 substituted aryl, and C7-12 arylalkyl esters of the compounds described herein may be preferred.
  • E3 ubiquitin ligase or “E3 ligase” refers to any protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin from the E2 protein to the protein substrate.
  • a “subject” to winch administration refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal.
  • the non-human animal is a mammal (e.g primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)).
  • primate e.g., cynomolgus monkey or rhesus monkey
  • commercially relevant mammal e.g., cattle, pig, horse, sheep, goat, cat, or dog
  • bird e.g., commercially relevant bird, such as chicken, duck, goose
  • the non-human animal is a fish, reptile, or amphibian.
  • the non-human animal may be a male or female at any stage of development
  • the non-human animal may be a transgenic animal or genetically engineered animal.
  • patient refers to a human subject in need of treatment of a disease.
  • an “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response.
  • An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject.
  • an effective amount is a therapeutically effective amount.
  • an effective amount is a prophylactic treatment.
  • an effective amount is the amount of a compound described herein in a single dose.
  • an effective amount is the combined amounts of a compound described herein in multiple doses.
  • a “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition.
  • the term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces, or avoids symptoms, signs, or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent.
  • a therapeutically effective amount is an amount sufficient for CDK binding and/or promoting the degradation of CDK9.
  • a therapeutically effective amount is an amount sufficient for treating a cancer.
  • cancer refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to infiltrate and destroy normal body tissues. See, e.g., Stedman’s Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990.
  • Exemplary cancers include, but are not limited to, hematological malignancies.
  • hematological malignancy refers to tumors that affect blood, bone marrow, and/or lymph nodes.
  • Exemplary' hematological malignancies include, but are not limited to, leukemia, such as acute lymphocytic leukemia (ALL) (e.g., B- cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL )); lymphoma, such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B- cell NHL, such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL, e.g., activated B-cell
  • Additional exemplary cancers include, but are not limited to, lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); kidney cancer (e.g., nephroblastoma, a.k.a.
  • lung cancer e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung
  • kidney cancer e.g., nephroblastoma, a.k.a.
  • Wilms tumor, renal cell carcinoma); acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangio sarcoma, lymphangioendotheliosarcoma, hemangio sarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary/ cancer, medullary' carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); chorio
  • myelofibrosis MF
  • chronic idiopathic myelofibrosis chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)
  • neuroblastoma e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis
  • neuroendocrine cancer e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor
  • osteosarcoma e.g., bone cancer
  • ovarian cancer e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma
  • papillary adenocarcinoma pancreatic cancer
  • pancreatic cancer e g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors
  • hematological cancer refers to cancer that begins in blood-forming tissue, such as the bone marrow, or in the cells of the immune system.
  • examples of hematologic cancer are leukemia, lymphoma, and multiple myeloma. Hematological cancer is also called blood cancer.
  • leukemia refers to broadly progressive, malignant diseases of the blood- forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow.
  • Leukemia diseases include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia
  • L comprises one or more linking groups selected from optionally substituted -C1-10 alkylene-, -O-C1-10 alkylene-, -C1-10 alkenylene-, -O-C1-10 alkenylene-, -C1-10 alkynylene-, -O-C1-10 alkynylene-, -arylene-, -heteroarylene-, -cycloalkylene-, - heterocycloalkylene-, -O-, -S-, -S-S-, -S(O) w -, -C(O)-, -C(O)O-, -OC(O)-, -C(O)S-, - SC(O)-, -OC(O)O-, -N(R b >, -C(O)N(R b )-, -N(R b )C(O)-, -OC(O)N(R b )-, -
  • E comprises an E3 ubiquitin ligase ligand moiety.
  • L comprises one or more linking groups selected from optionally substituted -C1-10 alkylene-, -O-C1-10 alkylene-, -C1-10 alkenylene-, -O-C1-10 alkenylene-, -C1-10 alkynylene-, -O-C1-10 alkynylene-, -arylene-, -heteroarylene-, -cycloalkylene-, - heterocycloalkylene-, -O-, -S-, -S-S-, -S(O) W -, -C(O)-, -C(O)O-, -OC(O)-, -C(O)S-, - -N(R b )-, -C(O)N(R b )-, -N(R b )C(O)-, -OC(O)N(R b )-, -N(R b )C(O)O-,
  • E comprises an E3 ubiquitin ligase ligand moiety
  • L comprises one or more linking groups independently selected from optionally substituted -C1-10 alkynylene-, -O-C1-10 alkynylene-, -arylene-, -heteroarylene-, -cycloalkylene-, and -heterocycloalkylene-.
  • L can comprise one linking group, two linking groups, three linking groups, four linking groups, or five linking groups independently selected from optionally substituted -C1-10 alkynylene-, -O-C1-10 alkynylene-, -arylene-, -heteroarylene-, -cycloalkylene-, and -heterocycloalkylene-.
  • L comprises at least two linking groups independently selected from optionally substituted -C1-10 alkynylene-, - heteroarylene-, and -heterocycloalkylene-.
  • L can comprise two linking groups, three linking groups, four linking groups, or five linking groups independently selected from optionally substituted -C1-10 alkynylene-, -heteroarylene-, and -heterocycloalkylene-.
  • L comprises at least two heterocycloalkylene groups.
  • L can comprise two heterocycloalkylene groups, three heterocycloalkylene groups, four heterocycloalkylene groups, or five heterocycloalkylene groups.
  • L comprises at least one piperidine moiety.
  • L can comprise one piperidine moiety, two piperidine moieties, or three piperidine moi eties.
  • L comprises at least one piperazine moiety.
  • L can comprise one piperidine moiety, two piperidine moieties, or three piperazine moieties.
  • L comprises at least one triazole moiety, such as a 1,2, 3 -triazole moiety'.
  • L can comprise one piperidine moiety, two piperidine moieties, or three triazole moieties
  • L comprises at least one alkynyl moiety.
  • L can comprise one piperidine moiety, two piperidine moieties, or three alkynyl moieties.
  • L comprises at least one azetidine moiety.
  • L can comprise one piperidine moiety, two piperidine moieties, or three azetidine moieties.
  • L comprises at least two moieties independently selected from a piperidine moiety, a piperazine moiety, a triazole moiety, such as a 1,2, 3 -triazole moiety, an alkynyl moiety, and an azetidine moiety.
  • L can comprise two moieties, three moieties, four moieties, or five moieties independently selected from a piperidine moiety, a piperazine moiety, a triazole moiety, such as a 1,2,3 -triazole moiety, an alkynyl moiety, and an azetidine moiety.
  • L comprises a piperidine moiety
  • L further comprises at least one additional linking group selected from optionally substituted -C1-10 alkynylene-, -O-C1-10 alkynylene-, -arylene-, -heteroarylene-, - cycloalkylene-, and - heterocycloalkylene.
  • L has a length of at least 8 atoms or at least 10 atoms, such as a length of from 8 atoms to 25 atoms, from 10 atoms to 25 atoms, from 8 atoms to 20 atoms, or from 10 atoms to 20 atoms.
  • L is not defined by the structure below
  • E can be any moiety that binds, or can bind, an E3 ubiquitin ligase.
  • E is capable of binding an E3 ubiquitin ligase, such as Cereblon or von Hippe! -Lindau tumor suppressor (VHL).
  • E is capable of binding to multiple different E3 ubiquitin ligases.
  • E binds to Cereblon.
  • E binds to VHL.
  • Non-limiting examples CRBN ligands include thalidomide, lenalidomide, pomalidomide, and any substructure thereof.
  • Any MDM2 ligand is contemplated by the present disclosure.
  • Non-limiting examples MDM2 ligands include idasanutlin, RG7112, RG7388, MI 773/S AR 405838, AMG 232, DS-3032b, RO6839921, RO5045337, RO5503781, CGM-097, MK-8242, and any substructure thereof.
  • Any VHL ligand is contemplated by the present disclosure.
  • Non-limiting examples MDM2 ligands include VHL ligand 1 (VHL- 1), VHL ligand 2 (VHL -2), VH032, and any substructure thereof. Examples of suitable E groups are discussed in more detail below.
  • CRBN Human Cereblon
  • Human CRBN contains the N-tenninal part (237-amino acids from 81 to 317) of ATP-dependent Lon protease domain without the conserved Walker A and Walker B motifs, 11 casein kinase II phosphorylation sites, 4 protein kinase C phosphorylation sites, 1 N-linked glycosylation site, and 2 myristoylation sites.
  • CRBN is widely expressed in testis, spleen, prostate, liver, pancreas, placenta, kidney, lung, skeletal muscle, ovary, small intestine, peripheral blood leukocyte, colon, brain, and retina.
  • CRBN is located in the cytoplasm, nucleus, and peripheral membrane.
  • Cereblon is an E3 ubiquitin ligase, and it forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB 1), Cullin-4A (CUL4A), and regulator of cullins 1 (ROCi ). This complex ubiquitinates a number of other proteins. Through a mechanism which has not been completely elucidated, Cereblon ubiquitination of target proteins results in increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8, in turn, regulates a number of developmental processes, such as limb and auditory vesicle formation.
  • FGF8 fibroblast growth factor 8
  • FGF10 fibroblast growth factor 10
  • E is a modulator, binder, inhibitor, or ligand of Cereblon. In certain embodiments, E is a modulator of Cereblon. In certain embodiments, E is a binder of Cereblon. In certain embodiments, E is an inhibitor of Cereblon. In certain embodiments, E is a ligand of Cereblon In certain embodiments, E is any modulator, binder, inhibitor, or ligand of Cereblon disclosed in U.S. Patent Application, U.S.S.N. 16/523,219, filed July 26, 2019; U.S. Patent Application, U.S.S.N. 16/502,529, filed July 3, 2019, U.S. Patent Application, U.S.S.N.
  • E is a modulator, binder, inhibitor, or ligand of a Cereblon variant. In certain embodiments, E is a modulator, binder, inhibitor, or ligand of a Cereblon isoform.
  • E is defined by Formula E-I :
  • each R B is a substituted or unsubstituted monocyclic, bicyclic, or tricyclic fused ring each R B is, independently, hydrogen, or substituted or unsubstituted alkyl; each R lA is, independently, halogen, OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy; each R jA is, independently, hydrogen or C 1 -C 3 alkyl; each R J is, independently, C 1 -C 3 alkyl, each R 4A is, independently, hydrogen or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 5A is hydrogen, C 1 -C 3 alkyl, F, or Cl; k is 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2 or 3; and
  • E is defined by Formula E-I-a:
  • R 5A is hydrogen, C 1 -C 3 alkyl, F, or Cl; k is 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2 or 3; and n is 0, 1, or 2.
  • E is of Formula E-I-b: each R B is, independently, hydrogen, or substituted or unsubstituted alkyl; each R 1A is, independently, halogen, OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy; each R 3A is, independently, hydrogen, or C 1 -C 3 alkyl; each R 3 is, independently, C 1 -C 3 alkyl; each R 4A is, independently, hydrogen or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6- membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 5A is hydrogen, C 1 -C 3 alkyl, F, or Cl; k is 0, 1 , 2, 3, 4, 5, or 6; m is 0, 1, 2 or 3; and n is 0, 1, or 2.
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl;
  • each R 1A is, independently, halogen, OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
  • each R 3A is, independently, hydrogen, or C 1 -C 3 alkyl;
  • each R J is, independently, C 1 -C 3 alkyl, each R 4A is, independently, hydrogen, or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6- membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 5A is hydrogen, C 1 -
  • X A is C(O) or C(R 3A ) 2 ;
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl;
  • each R 1A is, independently, halogen, OH, Ct-Ce alkyl, or C 1 -C 6 alkoxy;
  • each R 3A is, independently, hydrogen, or Ci- C 3 alkyl;
  • each R 3 is, independently, C 1 -C 3 alkyl;
  • each R 4A is, independently, H or Ci- Cs alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle
  • X A is C(O) or C(R 3A ) 2 ;
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl;
  • each R 1A is, independently, halogen, OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
  • each R jA is, independently, H or C 1 -C 3 alkyl;
  • each R J is, independently, Ci- C 3 alkyl;
  • each R 4A is, independently, H or C 1 -C 3 alkyl, or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle
  • E is defined by the formula below wherein Y, X A , R 5A , and R 4A are as defined above.
  • E is of Formula E-bd
  • X A is C(O) or C(R 3A ) 2 ; each R B is, independently, hydrogen, or substituted or unsubstituted alkyl; each R 3A is, independently, hydrogen or C 1 -C 3 alkyl; each R 4A is, independently, hydrogen or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6- membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 5A is hydrogen, Ct-C 3 alkyl, F, or Cl; and k is 0, 1, 2, 3, 4, 5, or 6.
  • X A is C(O) or C(R 3A ) 2 ;
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl;
  • each R 3A is, independently, H or C 1 -C 3 alkyl;
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 5A is hydrogen, C 1 -C 3 alkyl, F, or Cl; and k is 0, 1, 2, 3, 4, 5, or 6.
  • Y is -(CH 2 )k-NR B -;
  • X A is C(O) or C(R 3A )Z;
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl;
  • each R 3A is, independently, hydrogen or C 1 -C 3 alkyl;
  • each R 4A is, independently, hydrogen or Ci- C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6- membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 5A is hydrogen, C 1 -C 3 alkvl, F, or Cl, and k is 0, 1, 2, 3, 4, 5, or 6.
  • E is of Formula E-I-e
  • R 5A is hydrogen, C 1 -C 3 alkyl, F, or Cl; and k is 0, 1, 2, 3, 4, 5, or 6.
  • Y is -(CH 2 )k-NR B -; each R 3 is, independently, hydrogen, or substituted or unsubstituted alkyl; each R 4A is, independently, hydrogen or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6- membered heterocycle comprising I or 2 heteroatoms selected from N and O; R 5A is hydrogen, C 1 -C 3 alkyl, F, or Cl; and k is 0, 1, 2, 3, 4, 5, or 6.
  • E is of Formula E-I-f wherein:
  • R 5A is hydrogen, C 1 -C 3 alkyl, F, or Cl; and k is 0, 1, 2, 3, 4, 5, or 6.
  • Y is -(CH 2 )k-NR B -, each R B is, independently, hydrogen, or substituted or unsubstituted alkyl; each R 4A is, independently, hydrogen or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6- membered heterocycle comprising 1 or 2 heteroatoms selected from N and O; R 5A is hydrogen, C 1 -C 3 alkyl, F, or Cl; and k is 0, 1, 2, 3, 4, 5, or 6.
  • E is of formula E-I-g wherein:
  • X A is C(O) or C(R 3A ) 2 ; each R 4A is, independently, hydrogen, or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6- membered heterocycle comprising 1 or 2 heteroatoms selected from N and O; each R 3A is, independently, hydrogen, or C 1 -C 3 alkyl; and R 5A is hydrogen, Ci-Cr alkyl, F, or Cl.
  • X A is C(O).
  • E is of formula E-I-h wherein each R 4A is, independently, hydrogen or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6- niembered heterocycle comprising I or 2 heteroatoms selected from N and O; and R 5A is hydrogen, (':••( '; alkyl, F, or Cl.
  • E is of formula E-l-i wherein each R 4A is, independently, H or C 1 -C 3 alkyl, or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O; and R 5A is H, C 1 -C 3 alkyl, F, or Cl.
  • E is of Formula E-II
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl; each R 1A is, independently, halogen, OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy; each R 3A is, independently, hydrogen, or C 1 -C 3 alkyl; each R 3 is, independently, C 1 -C 3 alkyl; each R 4A is, independently, hydrogen, or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6- membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 5A is hydrogen, C 1 -C 3 alkyl, F, or Cl; k is 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2 or 3; and n is 0, 1 , or 2.
  • Y is -NH-.
  • Y is -(CH 2 )k-O-.
  • Y is -O-.
  • E is of formula E-II-a each R B is, independently, hydrogen, or substituted or un substituted alkyl; each R 1A is, independently, halogen, OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy; each R 3A is, independently, H or C 1 -C 3 alkyl; each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-metnbered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 5A is hydrogen, C 1 -C 3 alkyl, F, or Cl; k is 0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2, or 3.
  • ⁇ is -(CH 2 )k-, -(CH 2 )k-O-, -O)CH 2 )k-, - C(R' A )2-C(R 3A ) 2 ; each R B is, independently, hydrogen, or substituted or unsubstituted alkyl; each R f A is, independently, halogen, OH, Ci-Q alkyl, or Ct-Cealkoxy; each R- lA is, independently, H or C 1 -C 3 alkyl, each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising I or 2 heteroatoms selected from N and O; R 5A is hydrogen, C 1 -C 3 alkyl, F, or Cl, k is
  • E is of formula E-II-b each R B is, independently, hydrogen, or substituted or unsubstituted alkyl; each R 3A is, independently, H or C 1 -C 3 alkyl; each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 5A is hydrogen, C 1 -C 3 alkyl, F, or Cl; and k is 0, 1, 2, 3, 4, 5, or 6.
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl;
  • each R 3A is, independently , H or C 1 -C 3 alkyl, each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R ?A is hydrogen, Ci- C 3 alkyl, F,
  • E is of formula E-II-c
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl;
  • each R 3A is, independently, H or C 1 -C 3 alkyl;
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(0), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R’ A is hydrogen, C 1 -C 3 alkyl, F, or Cl; and k is 0, 1, 2, 3, 4, 5, or 6.
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl;
  • each R 3A is, independently, H or C 1 -C 3 alkyl;
  • each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(0), Cn-Ce carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R' A is hydrogen, Ci- C 3 alkyl, F, or Cl, and k
  • E is of formula E-II-d
  • each R B is, independently, hydrogen, or substituted or unsubstituted alkyl
  • each R 3A is, independently, H or C 1 -C 3 alkyl
  • each R 4A is, independently, H or C 1 -C 3 alkyl
  • two R 4A together with the carbon atom to which they are attached, form a C(O), Cj-Ce carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O; and
  • R 5A is hydrogen, C 1 -C 3 alkyl, F, or Cl.
  • E is defined by the formula below wherein each R 4A is, independently, H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form a C(O), C 3 -C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O; and R 5A is hydrogen, Ci- C 3 alkyl, F, or Cl.
  • E is The von Hippel-Lindau tumor suppressor (VHL) is an E3 ubiquitin ligase.
  • VHL comprises the substrate recognition subunit/E3 ubiquitin ligase complex VCB, which includes elongins B and C, and a complex including C lullin-2 and Rbxl.
  • the primary substrate of VHL is Hypoxia Inducible Factor la (HIF-la), a transcription factor that upregulates genes, such as the pro-angiogenic growth factor VEGF, and the red blood cellinducing cytokine, erythropoietin, in response to low oxygen levels.
  • VCB is a known target in cancer, chronic anemia, and ischemia.
  • VHL von Hippel -Lindau tumor suppressor protein
  • VHL has two main structural domains: an N-terminal domain composed mainly of b-sheets (b-domain) and a smaller C-termi na 1 domain between amino acids 155-192 composed mainly of a helices (a-domain).
  • the a- domain consists of three a helices that combines with a fourth a helix donated by elongin C.
  • the b-domain is on the opposite side of the a domain and is free to contact, other protein.
  • E is a modulator, binder, inhibitor, or ligand of VHL. In certain embodiments, E is a modulator of VHL. In certain embodiments, E is a binder of VHL. In certain embodiments, E is an inhibitor of VHL. In certain embodiments, E is a ligand of Cereblon. In certain embodiments, E is any ligand of VHL disclosed in U.S. Patent Application, U.S.S.N. 16/523,219, filed July 26, 2019; U.S. Patent Application, U.S.S.N. 16/375,643, filed April 4, 2019; U S Patent Application, U.S.S.N. 16/230,792, filed December 21, 2018, U.S.
  • E is a modulator, binder, inhibitor, or ligand of a VHL variant.
  • E is a modulator, binder, inhibitor, or ligand of a VHL isoform. In certain embodiments, E is a modulator, binder, inhibitor, or ligand of a VHL gene-product (e g., pVHL19).
  • VHL gene-product e g., pVHL19
  • E is of Formula (E-III):
  • W 3 is substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene,
  • R 9 and R 11 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted heteroaryl, or haloalkyl; or R ", R n , and the carbon atom to which they are attached form a substituted or unsubstituted cycloalkyl;
  • R 10 is -O-, -NH-, substituted or unsubstituted heterocyclylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted arylene;
  • R 14a and R 14b are each independently hydrogen, haloalkyl, or substituted or unsubstituted alkyl;
  • W 5 is aryl or heteroaryl
  • R 15 is hydrogen, halogen, CN, OH, NO 2 , -NR 14a R 14b , OR 14a , CONR 14a R 14b , NR 14a COR 14b , SO 2 NR l4a R 14b , NR 14a SO 2 R i4b , substituted or unsubstituted alkyl, haloalkyl, haloalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl; each R 16 is independently halo, substituted or un substituted alkyl, haloalkyl, hydroxy, haloalkoxy, or > wherein R is hydrogen, halogen, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstitute
  • X a is S or O, and o is 0, 1, 2, 3, or 4
  • E is of Formula E-III-a
  • E is of Formula E-III-a- 1
  • E is of Formula E-III-b
  • E is of Formula E-III-b-1
  • E is of Formula E-III-c E-III-c wherein R 35 and R 16 are as defined herein.
  • E is of Formula (E-III-c- 1 ):
  • E is of Formula E-III-d
  • E is of Formula E-III-d-1
  • E is of the formula:
  • E is of the formula:
  • E is of the formula:
  • E is of the formula:
  • the E3 ubiquitin ligase ligand moiety is selected from: wherein Y is selected from -N(R)-, -N(H)-, and -O-, wherein R is optionally substituted alkyl. In some embodiments, the E3 ubiquitin ligase ligand moiety is selected from:
  • the E3 ligase ligand moiety binds an E3 ubiquitin ligase with a Kd of less than 100,000 nM, less than 50,000 nM, less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM.
  • the E3 ligase ligand moiety binds Cereblon with a Kd of less than 100,000 nM, less than 50,000 nM, less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM.
  • the E3 ligase binding moiety binds VHL with a Kd of less than 100,000 nM, less than 50,000 nM, less than 20,000 nM, less than 10,000 nM, less than 5,000 nM, less than 2,500 nM, less than 1 ,000 nM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 90 nM, less than 80 nM, less than 70 nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM.
  • the E3 ligase ligand moiety selectively binds an E3 ubiquitin ligase as compared to another protein. In some embodiments, the E3 ligase ligand moiety selectively binds Cereblon over another protein. In some embodiments, the E3 ligase ligand moiety selectively binds Cereblon over another E3 ubiquitin ligase. In some embodiments, the E3 iigase ligand moiety selectively binds VHL over another protein. In some embodiments, the E3 ligase ligand moiety selectively binds VHL over another E3 ubiquitin ligase.
  • the selectivity is between about 2-fold and about 5- fold. In certain embodiments, the selectivity is between about 5-fold and about 1 O-fold. In certain embodiments, the selectivity is between about 10-fold and about 20-fold. In certain embodiments, the selectivity is between about 20-fold and about 50-fold. In certain embodiments, the selectivity is between about 50-fold and about 100-fold. In certain embodiments, the selectivity is between about 100-fold and about 200-fold. In certain embodiments, the selectivity is between about 200-fold and about 500-fold. In certain embodiments, the selectivity is between about 500-fold and about 1000-fold. In certain embodiments, the selectivity is at least about 1000-fold.
  • the compound in some examples of Formula I, can be defined by the formula below wherein n and n* are each independently an integer from 1 to 20, such as an integer from 1 to 15, an integer from 1 to 12, an integer from 1 to 10, an integer from 2 to 20, an integer from 2 to 15, an integer from 2 to 12, an integer from 2 to 10, an integer from 4 to 20, an integer from 4 to 15, an integer from 4 to 12, or an integer from 4 to 10.
  • the sum of n and n* can be from 8 to 14 (e.g., 8, 9, 10, 11, 12, 13, or 14).
  • the compound can be one of the following:
  • the compounds and compositions described herein can be used in methods for treating diseases and disorders.
  • the compounds and compositions described herein can be used in methods for treating diseases associated with the upregulation of myeloid cell leukemia-1 (Mcl-1) oncoprotein.
  • the compounds and compositions described herein can be used for the treatment of hyperproliferative disorders, including those hyperproliferative disorders associated with the upregulation of Mcl-1 .
  • the compounds and compositions described herein may also be used in treating other disorders as described herein and in the following paragraphs.
  • the disclosure provides a method of treating or preventing a disease or disorder alleviated by inhibiting Mcl-1 protein activity in a patient in need of said treatment or prevention. In some embodiments, the method comprises administering a therapeutically effective amount of one or more compounds of the disclosure, or a pharmaceutically acceptable salt thereof. In one aspect, the disclosure provides a method of treating or preventing a disease or disorder alleviated by indirectly inhibiting Mcl-1 protein activity in a patient in need of said treatment or prevention. In some embodiments, the method comprises administering a therapeutically effective amount of one or more compounds of the disclosure, or a pharmaceutically acceptable salt thereof.
  • the Mcl-1 protein activity is inhibited by the compounds of the disclosure binding to a target that downregulates and/or inhibits Mcl-1 protein activity.
  • the disclosure provides a method of treating or preventing a disease or disorder alleviated by inhibiting CDK9 protein activity in a patient in need of said treatment or prevention.
  • the method comprises administering a therapeutically effective amount of one or more compounds of the disclosure, or a pharmaceutically acceptable salt thereof.
  • the disclosure provides a method of treating or preventing a disease or disorder alleviated by indirectly inhibiting CDK9 protein activity in a patient in need of said treatment or prevention.
  • the method comprises administering a therapeutically effective amount of one or more compounds of the disclosure, or a pharmaceutically acceptable salt thereof.
  • the disease or disorder is cancer.
  • the cancer is selected from the cancer is selected from acute myeloid leukemia (AML), pancreatic cancer, breast cancer, prostate cancer, lymphoma, skin cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain carcinoma, head-neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck carcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma, small-cell lung carcinoma, Wilms’ tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostatic carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, adrenal cortex carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fun
  • AML acute mye
  • the cancer is a blood cancer.
  • the blood cancer is selected from acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic lymphoma (ALL), and chronic lymphocytic leukemia (CLL ), diffuse large B-cell lymphoma (DLBCL), primary’ mediastinal B-cell lymphoma, intravascular large B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma (SLL), mantle cell lymphoma, marginal zone B-cell lymphoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, and primary' central nervous system lymphoma.
  • AML acute myeloid leukemia
  • CML chronic myeloid leukemia
  • ALL acute lymphocytic lymphoma
  • the disclosure provides a method of treating or preventing acute myeloid leukemia (AML) in a patient in need of said treatment or prevention.
  • the method comprises administering a therapeutically effective amount of one or more compounds of the disclosure, or a pharmaceutically acceptable salt thereof.
  • the hyperproliferative disorder treated by the compounds and compositions described herein includes cells having Mcl-1 protein and/or Mcl-1 related protein expression.
  • the disease treated by the compounds and compositions described herein is selected from the group consisting of myeloid leukemia, non-small ceil lung cancer, pancreatic cancer, prostate cancer, and ovarian cancer.
  • the compounds described herein may induce cell cycle arrest and/or apoptosis in cells containing functional Mcl-1 proteins.
  • the compounds described herein may be used for sensitizing cells to additional agent(s), such as inducers of apoptosis and/or cell cycle arrest, and chemoprotection of normal cells through the induction of cell cycle arrest prior to treatment with chemotherapeutic agents.
  • the compounds described herein may be useful for the treatment of disorders, such as those responsive to induction of apoptotic cell death, e.g , disorders characterized by dysregulation of apoptosis.
  • the compounds may be used to treat cancer that is characterized by resistance to cancer therapies (e.g , those cancer cells which are chemoresistant, radiation resistant, hormone resistant, and the like).
  • cancer therapies e.g , those cancer cells which are chemoresistant, radiation resistant, hormone resistant, and the like.
  • the compounds can be used to treat hyperproliferative diseases characterized by expression of functional Mcl-1 and/or Mci-1 related proteins, which may or may not be resilient to BC1-XL inhibitors.
  • the methods provided herein further comprise administering one or more additional therapeutic agents to the subject.
  • each of the one or more additional therapeutic agents is independently selected from the group consisting of a steroid, an anti-allergic agent, an anesthetic (e.g., for use in combination with a surgical procedure), an immunosuppressant, an anti-microbial agent, an antiinflammatory agent, and a chemotherapeutic agent.
  • Example steroids include, but are not limited to, corticosteroids such as cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, and prednisone.
  • corticosteroids such as cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, and prednisone.
  • Example immunosuppressants include, but are not limited to, azathioprine, chlorambucil, cyclophosphamide, cyclosporine, daclizumab, infliximab, methotrexate, and tacrolimus.
  • Example anti-microbial agents include, but are not limited to, aminoglycosides (e.g., gentamicin, neomycin, and streptomycin), penicillins (e.g., amoxicillin and ampicillin), and macrolides (e.g., erythromycin).
  • aminoglycosides e.g., gentamicin, neomycin, and streptomycin
  • penicillins e.g., amoxicillin and ampicillin
  • macrolides e.g., erythromycin
  • Example anti-inflammatory agents include, but are not limited to, aspirin, choline salicylates, celecoxib, diclofenac potassium, diclofenac sodium, diclofenac sodium with misoprostol, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, meclofenamate sodium, mefenamic acid, nabumetone, naproxen, naproxen sodium, oxaprozin, piroxicam rofecoxib, salsalate, sodium salicylate, sulindac, tolmetin sodium, and valdecoxib.
  • Example chemotherapeutics include, but are not limited to, proteosome inhibitors (e.g., bortezomib), thalidomide, revlimid, and DNA-damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine, and the like.
  • proteosome inhibitors e.g., bortezomib
  • thalidomide thalidomide
  • revlimid thalidomide
  • DNA-damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine, and the like.
  • one or more of the following agents may be used in combination with the compounds provided herein and are presented as a non-limiting list: a cytostatic agent, cisplatin, taxol, etoposide, irinotecan, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, temozolomide, cyclophosphamide, gefitinib, erlotinib hydrochloride, imatinib mesylate, gemcitabine, uracil mustard, chlormethine, ifosfamide, chlorambucil, pipobroman, tri ethylenemelamine, tri ethylenethiophosphoramine, busulfan, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6- thioguanine, fludarabine phosphate, oxaliplatin,
  • an active pharmaceutical ingredient or combination of active pharmaceutical ingredients such as any of the CDK9 degraders described herein, is provided as a pharmaceutically acceptable composition.
  • the concentration of each of the active pharmaceutical ingredients provided in the pharmaceutical compositions of the disclosure is less than, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w/w, w/v or v/
  • the concentration of each of the active pharmaceutical ingredients provided in the pharmaceutical compositions of the disclosure is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.7
  • the concentration of each of the active pharmaceutical ingredients provided in the pharmaceutical compositions of the disclosure is in the range from about 0.0001% to about 50%, about 0.001% to about 40%, about 0.01% to about 30%, about 0,02% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1 % to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12% or about 1% to about 10% w/w, w/v or v/v of the pharmaceutical composition.
  • the concentration of each of the active pharmaceutical ingredients provided in the pharmaceutical compositions of the disclosure is in the range from about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0 07% to about 2%, about 0 08% to about 1.5%, about 0.09% to about 1%, about 0.1% to about 0.9% w/w, w/v or v/v of the pharmaceutical composition.
  • the amount of each of the active pharmaceutical ingredients provided in the pharmaceutical compositions of the disclosure is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5 5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3 0 g, 2.5 g, 2.0 g, 1 5 g, 1.0 g, 0.95 g, 0 9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0 65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 s, 0.08 g, 0.07 g, 0.06 g, 0.05 g,
  • the amount of each of the active pharmaceutical ingredients provided in the pharmaceutical compositions of the disclosure is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0 0085 g, 0 009 g, 0.0095 g, 0.01 g, 0.015 g, 0 02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05
  • the active pharmaceutical ingredients described herein can be effective over a wide dosage range.
  • dosages independently range from 0.01 to 1000 mg, from 0.5 to 100 mg, from I to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used.
  • the exact dosage will depend upon the route of administration, the form in which the compound is administered, the gender and age of the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician Clinically-established dosages of the CDK9 degraders described herein may also be used if appropriate.
  • the molar ratio of two active pharmaceutical ingredients in the pharmaceutical compositions is in the range from 10:1 to 1:10, preferably from 2.5:1 to 1 :2.5, and more preferably about 1:1.
  • the weight ratio of the molar ratio of two active pharmaceutical ingredients in the pharmaceutical compositions is selected from the group consisting of 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, and 1:20.
  • the weight ratio of the molar ratio of two active pharmaceutical ingredients in the pharmaceutical compositions is selected from the group consisting of 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, 10:1,9:1,8:1,7:1,6:1,5:1,4:1,3:1,2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, and 1:20.
  • the disclosure provides a pharmaceutical composition comprising one or more of the CDK9 degraders described herein, or a pharmaceutically acceptable salt thereof, and a physiologically compatible carrier medium (also referred to as an excipient).
  • a pharmaceutical composition for treating or preventing a disease or disorder alleviated by inhibiting CDK9 protein activity the pharmaceutical composition comprising one or more CDK9 degraders described herein, or a pharmaceutically acceptable salt thereof, and a physiologically compatible carrier medium.
  • the disease or disorder is cancer.
  • the disclosure provides a pharmaceutical composition for treating or preventing a disease or disorder alleviated by indirectly inhibiting CDK9 protein activity, the pharmaceutical composition comprising one or more CDK9 degraders described herein, or a pharmaceutically acceptable salt thereof, and a physiologically compatible carrier medium.
  • the disease or disorder is cancer.
  • the cancer is selected from acute myeloid leukemia (AML), pancreatic cancer, breast cancer, prostate cancer, lymphoma, skin cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain carcinoma, head-neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck carcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma, small -cell lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostatic carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, adrenal cortex carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, mal
  • the cancer is a blood cancer.
  • the blood cancer is selected from acute myeloid leukemia (AMI..), chronic myeloid leukemia (CML), acute lymphocytic lymphoma (ALL), and chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, intravascular large B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma (SLL), mantle cell lymphoma, marginal zone B-cell lymphoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, and primary central nervous system lymphoma.
  • AMI.. acute myeloid leukemia
  • CML chronic myeloid leukemia
  • ALL acute lymphocytic lymphoma
  • the described methods of treatment may normally include medical follow-up to determine the therapeutic or prophylactic effect brought about in the subject undergoing treatment with the cotnpound(s) and/or composition(s) described herein.
  • the disclosure provides a pharmaceutical composition for treating or preventing from acute myeloid leukemia (AML), the pharmaceutical composition comprising one or more CDK9 degraders described herein, or a pharmaceutically acceptable salt thereof, and a physiologically compatible earner medium. Described below are non-limiting pharmaceutical compositions.
  • the CDK9 degraders described herein can be administered in the form of pharmaceutical compositions.
  • These compositions can be prepared as described herein or elsewhere, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery'), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral, or parenteral.
  • topical including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery'
  • pulmonary e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal
  • oral or parenteral.
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, (e.g., intrathecal or intraventricular, administration).
  • Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump.
  • the compounds provided herein, or a pharmaceutically acceptable salt thereof are suitable for parenteral administration.
  • the compounds provided herein are suitable for intravenous administration
  • the compounds provided herein are suitable for oral administration
  • the compounds provided herein are suitable for topical administration.
  • compositions and formulations for topical administration may include, but are not limited to, transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders.
  • Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
  • the pharmaceutical compositions provided herein are suitable for parenteral administration.
  • the pharmaceutical compositions provided herein are suitable for intravenous administration.
  • the pharmaceutical compositions provided herein are suitable for oral administration.
  • the pharmaceutical compositions provided herein are suitable for topical administration.
  • compositions which contain, as the active ingredient, a compound provided herein in combination with one or more pharmaceutically acceptable carriers (e.g. excipients).
  • the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be, for example, in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • excipients include, without limitation, lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include, without limitation, lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; flavoring agents, or combinations thereof.
  • the active compound can be effective over a wide dosage range and is generally administered in an effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual subject, the severity of the subject’s symptoms, and the like.
  • compositions provided herein can be administered one from one or more times per day to one or more times per week; including once every other day.
  • the skilled artisan will appreciate that certain factors can influence the dosage and timing required to effectively treat a subject, including, but not limited to, the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present.
  • treatment of a subject with a therapeutically effective amount of a compound described herein can include a single treatment or a series of treatments.
  • Dosage, toxicity and therapeutic efficacy of the compounds provided herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g:, for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50.
  • Compounds exhibiting high therapeutic indices are preferred. While compounds that exhibit toxic side effects can be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.
  • Example 1 Design and Synthesis of CDK9-Targeting Protein Degraders for the Achievement of Improvement of Potency and Physicochemical Properties
  • AML Acute Myeloid Leukemia
  • Current therapies for AML have low efficacy and/or high toxicity.
  • Proteolysis Targeting Chimeras also called degraders, are heterobifunctional molecules that contain a ligand for a target protein tethered through a linker to another ligand for an E3 Ligase complex within cells.
  • the E3 ligase complex tags the target protein through proximity-induced ubiquitination, and this is followed by degradation by a proteasome. This mechanism of action allows a single PROTAC molecule to degrade multiple proteins, affording a catalytic process.
  • PROTAC activity is an opportunity for lower dosing in AML patients, reducing the toxicity observed in current chemotherapies.
  • PROTAC technology has been shown to be less vulnerable to resistance development, a current and significant hurdle in the development of cancer therapeutics. This is because of the ability to completely degrade a target protein, without the limitation of the reliance on strong binding that drives the activity of traditional inhibitors.
  • CDK9 Cyclin Dependent Kinase pathway
  • MCL-1 and MYC pro-survival genes
  • THAL thalidomide
  • CRBN Cereblon
  • a combinatorial approach was employed that involves click chemistry, a cycloaddition between an alkyne and an azide, that tethers CDK9-recruiter precursors to CRBN recruiter precursors.
  • a significant advantage of this approach is the ability to use fragments from each compound library to generate PROTACs containing a variety of warheads for different targets and ultimately, different cancers.
  • Multiple AT-7519-inspired CDK9 degraders were synthesized utilizing this chemistry, most of which demonstrated low nanomolar activity against. AML cells.
  • VIP152 also referred to as BAY1251152 or B2
  • This transition is important because AT-7519 is a pan-CDK inhibitor and its lack of selectivity 7 was observed in its degraders.
  • the potency and selectivity of VIP 152 can be conferred onto its degrader form.
  • Atuveciclib another potent and selective CDK9 inhibitor, can be incorporated into a CRBN-recruiting degrader, B03.
  • B03 exhibits high potency and selectivity, along with in vivo efficacy.
  • Solvents like PEG400 and DMSO are sometimes used in formulations to solubilize highly lipophilic compounds during in vivo testing. However, these compounds present some toxicity concerns.
  • simple aqueous solutions like phosphate buffered saline (PBS), as IV vehicles have been shown to be less toxic and to be isotonic relative to human plasma, a property that is important to the safety of IV drugs.
  • PBS phosphate buffered saline
  • AT7519 was chosen as the first warhead to incorporate into a degrader due to its potency, synthetic feasibility, and structural data that confirmed the presence of a synthetically useful linker attachment handle.
  • the piperidine ring in AT7519 extends outside of the ATP- binding pocket within CDK2, a homolog of CDK9 within which the gene sequence encoding the binding pocket is conserved across CDKs. Therefore, the piperidine nitrogen can be used as an attachment point for the assembly of AT7519-based degraders.
  • Solvents such as dimethyl sulfoxide (DMSO), polyethylene glycol and Tween 80®, had to be added in generous quantities to the PBS vehicle to facilitate solubility of the test compounds and allow for the preliminary in vivo assessment that led to the conclusion of inactivity in mice.
  • C hem Axon logarithm are also provided for each degrader.
  • two additional assays were performed: a kinetic aqueous solubility assay and the chromatographic logD experiment described earlier. Aqueous solubility is shown in ⁇ M while experimentally determined logD is shown as logk’80, Details regarding the execution of each experiment are provided below.
  • the cytotoxicity data showed that a significant portion of the degraders in the click series (4.8, 4.9a-c and 4.10) were able to achieve low nanomolar potency against MV411 cells, outperforming AT7519 in the same cell line. Most importantly, certain degraders demonstrated downstream repression of the anti-apoptotic gene MCL-1, as determined by western blots obtained from drugged MOLM13 cells ( Figure 1). To better evaluate the catalytic mechanism of action of this degrader series, a drag washout (WO) experiment was performed. This experiment involved the drugging of cells for six hours after which the cell media was replaced with a drug-free batch.
  • WO drag washout
  • the impact of the triazole is also notable when examining the aqueous solubility values within the 4.7 set.
  • a notable difference in aqueous solubility is observed between 4.7a and 4.7c from simply moving the rigid triazole by one methylene unit closer to one ligand over the other.
  • the presented data also show that beyond the 4.8 set, the aqueous solubility of the degraders begin to stay below 5 ⁇ M.
  • 4.7b is able to demonstrate the highest aqueous solubility within the series, 40 ⁇ M, likely due to its low predicted logD and low measured logk’80.
  • FBS (as known as “a protein shift”) is usually associated with the binding of drugs to the plasma proteins that are present to a significantly higher degree in HS, as opposed to FBS. Therefore, the low lipophilicity (according to logk’80) and higher aqueous solubility of 4.7b is likely the reason for the lack of a protein shift for the degrader. This contrasts with 4.8a, which loses its potency by almost 20-fold in human serum (Figure 3C). Interestingly, 4.9c only loses its potency in human serum by 3-fold, while still maintaining superior potency over other analogues within both FBS and HS ( Figure 3B).
  • VIP152 (3.19) is one of the most potent and selective CDK9 inhibitors reported to date. The small molecule has been shown to be effective in repressing MCL-1 and BCL-2 anti-apoptotic genes in different hematological disorders, including in AML and chronic lymphocytic leukemia (CLL). Therefore, VIP 152 was chosen for the next phase of the CDK9 degrader development project.
  • Racemic VI P 152 (4.16) would first be synthesized using the route presented in Scheme 5. This scheme follows the synthetic approach that was used in the original patent in which the discovery of VIP152 was first reported.
  • the route began with a Suzuki coupling between the aryl iodide 4.17 and boronic acid 4.18, using [1,T- Bis(diphenylphosphino)ferrocene]di chloropalladium (II) as the catalyst
  • the reaction cleanly provided intermediate 4.19 in high yield.
  • a nucleophilic aromatic substitution 4.19, was then reacted with the amine 4.20, at high temperature with sodium tert-butoxide to provide the alcohol 4.21.
  • the degraders within the initial series were able to demonstrate low nanomolar cytotoxicity against MOLM13 cells, with degrader 4.34 showing comparable potency to the parent warhead, 4.16.
  • none of the degraders in the series showed significant aqueous solubility.
  • the lack of good aqueous solubility was surprising, especially for degrader 431 which shares the same structural design as its AT7519 analogue, 4.7b.
  • the high lipophilicity of 4.31 and 4.34 set the stage for the challenges that would follow in the design of this new degrader series.
  • the VIP 152 alkyne derivative 4.35 was synthesized according to Scheme 8. This alkyne intermediate would incorporate a piperazine ring, a modification that was expected to increase aqueous solubility based on the ability of the piperazine to ionize at physiological pH (pKa ⁇ 10).
  • Compound 4.35 was synthesized by reacting Boc- protected piperazine 4.36 with propargyl bromide in an SN 2 reaction to produce 4.37a which was treated with trifluoroacetic acid (TFA) to obtain 4.37b Under the same basic conditions, 4.37b was reacted with tert-butyl 2-bromoacetate to produce the pivoyl ester of 4.38. Using the same TFA conditions for the tert-butyl deprotection, the carboxylic acid, 4.38 was obtained and reacted under EDC coupling conditions with 4.16 to obtain 4.35, The alkyne was then reacted under click chemistry conditions to produce the first VIP 152-based degrader bearing a saturated heterocyclic linker, 4.39.
  • TFA trifluoroacetic acid
  • Scheme 9 Synthesis of first series of azetidine and piperazine-containing IMiD azides; 4.40-4.42.
  • Scheme 10 presents the structures of the first series of the heterocyclic click series that was generated using the VI Pl 52-based alkyne 4.35 and the three IMiD azides 4.40, 4.41 and 4.42.
  • the evaluation of 4.49, 4.50 and 4.51 would then reveal some opportunities for improving physicochemical properties while setting realistic expectations with regard to the effect on potency from reducing lipophilicity (Table 4). This is seen from the results of characterizing degrader 4.49 compared to 4.50 and 4.51 This compound is able to achieve near 60 ⁇ M aqueous solubility. However, the compound shows only modest potency (420 nM).
  • Boe-protected ethynyl piperidine 4.54 was treated with TFA and subjected to reductive amination with sodium triacetoxyborohydride to produce the ester 4.56, Following hydrolysis of the ester under basic conditions, the resulting acid was coupled using EDC.HC1 to 4.16, to obtain 4.52, Alkylation of the nipecotate ester 4.57 afforded the propargyl derivative 4.58. The hydrolysis afforded the carboxylic acid derivative which was used in the same EDC.HC1 amide coupling procedure to produce 4.53.
  • the synthesis of the two new alkynes would also contribute to the generation of valuable intermediates that could be used in a combinatorial manner along with synthesized IMiD azides to generate a diverse degrader library.
  • the results of the characterization of these PROTACs are shown in Table 5. The data show that the use of the two new piperidine-containing alkyne intermediates favored potency.
  • IMiD derivatives 4.41 and 4.42 resulted in degraders with overall lower potency, particularly cytotoxicity This is based on the loss of activity observed with degraders 4.60 and 4,64.
  • the amide- containing azetidine analogue 4.59 was able to recover the potency lost in its piperazine analogue 4.49.
  • the intermediate 4.69a was synthesized from ethynyl piperidine 4.54 and subsequently deprotected using TFA.
  • the resulting amine 4.69b was then coupled to azidoacetic acid 4.48 as was performed with 4.65, to obtain IMiD azide 4.66.
  • the iodomethyl piperidine 4.70 was reacted with sodium azide with high heating to produce 4.71a, in good yield.
  • the Boc -protected intermediate was then treated with TFA to obtain the piperidine azide 4.71b.
  • the amine was then subjected to a nucleophilic aromatic substitution with 4.45 to obtain the desired IMiD azide product 4.67.
  • the degraders were synthesized according to Scheme 14 and rapidly provided the desired PROTACs. The reduction of the alkynyl linkage in the imide azide 4.42 was performed to add a level of conformational flexibility that was expected to favor binding to the CRBN E3 ligase, while retaining the modest aqueous solubility that was observed in degrader 4.64.
  • IMiD derivatives Table 4.6, Cytotoxicity, degradation potency and physicochemical properties of third VIP152-based heterocyclic dick series. After this third series, the IMiD azide and VIP-152 alkyne derivative libraries had been explored for the generation of a diverse set of tri azol e-containing PROTACs.
  • the bipiperidine derivative 4.81 was obtained The product was reacted with bromoacetic acid to afford the acid derivative 4.82 which was coupled to 4.16 using EDC.HC1. Similarly, to obtain the degrader 4.79, 4.80 was reacted with bromoacetic acid, resulting in the acetic acid derivative 4.83b. The obtained product was then coupled to 4.16 under the same amide coupling conditions as 4.78 to afford degrader 4.79.
  • the oxoazetidine 4.86 was reacted in a reductive amination with the piperazine azide 4.71b.
  • the acquired product was treated with TEA to obtain the free azetidine 4.87b which was reacted with 4.2 under amide coupling conditions to afford 4.84.
  • the carboxylic acid derivative 4.88 would first be synthesized through amide coupling with succinic acid. The product would then be reacted with 4.87b using EDC.HCI as the coupling reagent to afford the desired azide-linked precursor, 4.85.
  • Figure 5 provides a labeled graphical plot of measured solubility against lipophilicity that indicates the compound corresponding to a particular data point.
  • the polar degraders in the upper-left quadrant of the plot it was found that they possess, on average, higher TPS.A and molecular weight.
  • the same review of calculated properties for the amphiphilic degraders reveals that the compounds possess lower molecular weight and TPSA than average and do not contain any hydrogen bond donors within their linkers.
  • the four degraders (4.49, 4.62, 4.72 and 4.78) were selected for a protein-shift analysis due to their higher potency and solubility.
  • the most potent degrader 4.34 was also selected for this analysis to determine if its high potency would be retained in human serum.
  • the data are provided in Table 9. The data show' that despite the high potency of 4.34 in fetal bovine serum, the degrader was outperformed by every other degrader when tested in human serum. In particular, 4.78 and 4.72 were able to retain their cytotoxic activity against the MOLM13 cells in human serum Interestingly, the other two polar degraders, 4.49 and 4.62, lose their potency significantly.
  • Scheme 18 illustrates the synthesis of two key' linker building blocks for the next degraders: 4,94 and 4,95
  • the synthesis of the degraders was facilitated by the gram-scale synthesis of the piperidine- and piperazine-containing alkynes 4.96 and 4,97.
  • Reagents used were purchased from commercial sources, as reagent grade quality chemicals, and were used without further purification.
  • AT7519 was synthesized as the TFA salt as previously described.
  • 4-hydroxy thalidomide was also synthesized using a previously reported synthetic scheme.
  • Reactions that required inert conditions were performed under argon atmosphere.
  • Reactions were monitored using Thin-Layer Chromatography (TLC) on silica gel plates with aluminum backing. Mass spectrometry was also used to monitor reaction progress as needed.
  • Normal phase (NP) chromatography was run manually using silica gel while reversed phase (RP) purifications were run on C18 RediSep columns on a Teledyne Isco CombiFlash system.
  • KS Kinetic solubility Assay.
  • Kinetic solubility (KS) was measured according to Millipore protocol PC2445EN00. Test compounds were weighed and diluted with DMSO to 10 mM. From the stock solutions as well as blank (100% DMSO) was taken 17.5 ⁇ L and diluted to 500 ⁇ M with 332.5 ⁇ L of 100 mM phosphate Buffered Saline (PPBS) at pH 7.4 in a 96-well quartz plate. From the 500 ⁇ M solutions was taken 150 ⁇ L and dispensed into a 96-well Millipore filter plate (Product number: MSSLBPC10).
  • PPBS phosphate Buffered Saline
  • reaction was allowed to proceed at room temperature for 26 hours under argon.
  • the reaction mixture was then dissolved in brine and extraction was performed with 20% MeOH in DCM.
  • the combined organic layers were dried over sodium sulfate, filtered, then concentrated under reduced pressure.
  • the residue was purified by column chromatography (SiO 2 , 7-10% MeOH in DCM) to provide 4.7a as a white solid (13 mg, 30% yield).
  • reaction was allowed to proceed at room temperature for 19.5 hours under argon. Hie reaction mixture was then dissolved in brine and extraction was performed with 20% MeOH in DCM. The combined organic layers were dried over sodium sulfate, filtered, then concentrated under reduced pressure. The residue was purified by column chromatography (SiOz, 7% MeOH in DCM) to provide 4.8a as a white solid (19.3 mg, 40% yield).
  • reaction was allowed to proceed at room temperature for 26.5 hours under argon). The reaction mixture was then dissolved in brine and extraction was performed with 20% MeOH in DCM. The combined organic layers were dried over sodium sulfate, filtered, then concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 , 7% MeOH in DCM) to provide 4.9a as a white solid (42.3 mg, 77% yield).
  • Butane- 1,4-diol (10.00 g, 111 mmol), TEA (6.18 g, 61.0 mmol), DMAP (1.36 g,
  • 6-azidohexan-l-ol 4.12c (4.4 g, 31 mmol), TEA (9.4 g, 93 mmol), were stirred in DCM (0.67M) at 0°C.
  • p-toluenesulfonyl chloride (8,86 g, 47 mmol) was added to the stirring mixture portionwise and allowed to stir at room temperature overnight Hie mixture was dissolved in ammonium chloride solution and extracted with DCM. The combined organic layers were washed with brine and dried over sodium sulfate, then concentrated under reduced pressure.
  • the pH of the mixture was adjusted to >10 by dropwise addition of 2 M KOH.
  • Oxone (648 mg, 1.05 mmol) was then added to the stirring mixture and the reaction proceeded for 3 hours, during which the pH was kept above 10.
  • the reaction mixture was filtered through a Whatman filter which was rinsed with plenty of DCM.
  • the filtrate was then washed with brine followed by an aqueous solution of sodium thiosulfate.
  • the recovered organic layer was concentrated under reduced pressure and the desired product 4.16 was isolated as an off-white powder (322 mg, 64% yield) from the mixture through suction filtration while rinsing with DCM and diisopropyl ether. Spectroscopic data are consistent with those reported previously.
  • 2-chIoro-5 ⁇ nuoro-4-(4 ⁇ fhmro ⁇ 2-methoxyphenyl)pyridme (4.19): 2-chloro-5-fluoro-4-iodopyridine (7.0 g, 27.2 mmol), (4-fluoro-2- methoxyphenyljboronic acid (4,62 g, 27.2 mol), 1,T- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.0 g, 2.72 mmol) and tripotassium phosphate (11.5 g, 54.4 mmol) were dissolved in DME (0.4 M) and the mixture was purged with argon.
  • the reaction mixture was then subjected to heat at 100°C and allowed to stir overnight.
  • the reaction was then concentrated unde rreduced pressure, dissolved in water and extracted multiple times with DCM.
  • the combined organic layers were washed with brine and dried over NazSCU, then filtered.
  • the crude mixture was then loaded onto SiO 2 and rinsed with ethyl acetate.
  • the resulting filtrate was purified by column chromatography (SiO 2 , 0-10% ethyl acetate in hexanes) to provide 4.19 as a colorless liquid (5.34 g, 77% yield). Spectroscopic data are consistent with those previously reported.
  • reaction mixture was then subjected to heat at 110°C and allowed to stir overnight.
  • the reaction was then concentrated under reduced pressure, dissolved in water and extracted multiple times with DCM.
  • the combined organic layers were washed with brine and dried over Na 2 SO 4 , then filtered.
  • the crude mixture purified by column chromatography (SiO 2 , 5-50% ethyl acetate in hexanes) to provide 4.21 as a colorless liquid (1 ,75g, 44% yield). Spectroscopic data are consistent with those previously reported in the literature.
  • N-(4-(chloromethyl)pyridin-2-yl) ⁇ 5-fluoro-4-(4-fluoro-2-methoxyphenyr)pyridin-2- amine 4.22 (300 mg, 0.83 mmol) was dissolved in EtOH (0.08M) and the solution was cooled to 0°C. Sodium thiomethoxide (131 mg, 1.87 mmol) was then added portionwise after which the reaction mixture was stirred at room temperature overnight. The reaction mixture was dissolved in brine then extracted with DCM. The combined organic layers were concentraed under reduced pressure to provide 4.22 an orange solid in quantitative yield. The product was taken onto the next step without further purification. Spectroscopic data are consistent with those previously reported in the literature.
  • Trifluoroacetamide (254 mg, 2.25 mmol) and sodium tert-butoxide (189 mg, 1.97 mmol) were dissolved in anhydrous THF (2 M) under inert atmosphere. The resulting mixture was cooled to 0°C after which a solution of l,3-dibromo-5,5- dimethylimidazolidine-2, 4-dione (268 mg, 0.94 mmol) in THF (0.9 M) was added slowly.
  • reaction mixture was then added slowly to a solution of 5-fluoro-4-(4-fluoro-2- methoxyphenyl)-N-(4-((methylthio)methyl)pyridin-2-yl)pyridin-2-amine 4.23 ( 700 mg, 1.87 mmol) in THF (1.2 M) at 0°C.
  • the reaction temperature was kept beiow 10°C for 2.5 hours, after which the reaction was quenched with an aqueous solution of sodium sulfite and toluene.
  • the resulting mixture was then exteracted multiple times with ethyl acetate.
  • the combined organic layers were washed w'ih brine and filtered through a Whatman filter.
  • Hept-6-ynoic acid (43.4 mg, 0 727 mmol, 1.1 equiv.), DMAP (66.5 mg, 0.544 mmol, 2.2 equiv.), EDC-HC1 (94.8 mg, 0.495 mmol, 2 equiv.) and VIP152 (4.16) (100 mg, 0.247 mmol, 1 equiv ) were reacted according to general procedure A to provide 4.29 as a white powder (104 mg, 82% yield).
  • Pent-4-ynoic acid (24.3 mg, 0.247 mmol, 1 equiv.), DMAP (66 5 mg, 0.544 mmol,
  • l-(prop"2-yn-l-yl)pjperazine (4.37b): tert-butyl piperazine-1 -carboxylate 4.36 (1 g, 5 37 mmol, 1 equiv.), dipotassium carbonate (1.48g, 10.7 mmol, 2 equiv.) and 3 -bromoprop- 1-yne (639 mg, 5.37 mmol, 1 equiv.) were dissolved in ACN (13.4 mL 0.4 M) and heated at 50 °C overnight. The reaction mixture was filtered the filtrate was concentrated under reduced pressure.
  • the purified material was dissolved in TFA (1.6 M), stirred for thirty minutes and concentrated under reduced pressure to afford 4.37b, and taken directly onto the next step.
  • 3-azidoazetidine (4.44) (226 mg, 1.75 mmol, 1 equiv.), 2- ⁇ [2-(2, 6-dioxopiperidin-3- yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-4-yl]amino ⁇ acetic acid (4.2) (331 mg, 0.875 mmol, 1 equiv.), HATU (399 mg, 1 .05 mmol, 1.2 equiv ) and DIPEA (226 mg, 1.75 mmol, 2 equiv.) were dissolved in DMF (21.9 mL, 0.04 M). The mixture was stirred overnight at room temperature.
  • tert-butyl 3-bromoazetidine-l -carboxylate 4.43 were dissolved in DMF (21.2 mL, 0.2 M) and heated to 80°C. The reaction mixture was concentrated under reduced pressure and dissolved in DCM. The solution was washed with water and the aqueous layer was extracted multiple times with DCM. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford tertbutyl 3-azidoazetidine-l-carboxylate (700 mg, 83% yield). Spectroscopic data are consistent with those previously reported in the literature.
  • reaction mixture was concentrated under reduced pressure and the erode mixture was purified by reversed phase chromatography (C18, 0-100% ACN in water) to afford tert-butyl 4-(3-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)prop- 2-yn-l-yl)piperazine-l -carboxyl ate 4.47a as a brown crystalline solid (380 mg, 107% yield).
  • the recovered solid was dissolved in TFA (1.6 M) and stirred at room temperature for one hour.
  • the reaction mixture was then concentrated under reduced pressure and purified by normal phase chromatography (SiO 2 , DCM:MeOH eluent) to provide 4.81.
  • reaction was quenched with a saturated solution of sodium carbonate, concentrated under reduced pressure and purified by reversed phase chromatography (C18, H 2 O:ACN eluent) to provide 4.96 (663 mg, 33% yield) as a clear colorless oil.

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Abstract

L'invention concerne des agents de dégradation de CDK9 qui comprennent une fraction de liaison à CDK9, telle que AT7519 ou VIP152, conjuguée à une fraction de liaison à l'ubiquitine ligase E3, telle que le thalidomide, le lénalidomide ou le pomalidomide. Ces agents de dégradation peuvent induire l'ubiquitination de CDK9 et favoriser sa dégradation dans des cellules. Le lieur liant de manière covalente la fraction de liaison à CDK9 à la fraction de liaison à l'ubiquitine ligase E3 peut être sélectionné pour accorder le profil de solubilité et la puissance de l'agent de dégradation. Par conséquent, la présente divulgation concerne des composés, des compositions, des kits, des utilisations et des procédés pour le traitement du cancer (par exemple, des cancers du sang tels que la leucémie aiguë myéloïde ou la leucémie lymphoblastique aiguë).
PCT/US2023/016989 2022-03-30 2023-03-30 Agents de dégradation de kinase 9 dépendante des cyclines (cdk9) et procédés d'utilisation associés WO2023192534A1 (fr)

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US202263397642P 2022-08-12 2022-08-12
US63/397,642 2022-08-12
US202263415718P 2022-10-13 2022-10-13
US63/415,718 2022-10-13

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Cited By (2)

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CN117736187A (zh) * 2024-02-19 2024-03-22 天津匠新致成科技有限公司 一种蛋白水解靶向嵌合体及其制备方法、药物组合物和应用
US12097261B2 (en) 2021-05-07 2024-09-24 Kymera Therapeutics, Inc. CDK2 degraders and uses thereof

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US20190119289A1 (en) * 2016-04-06 2019-04-25 The Regents Of The University Of Michigan Monofunctional intermediates for ligand-dependent target protein degradation
WO2020172655A1 (fr) * 2019-02-23 2020-08-27 New York University Photac photocommutables et leur synthèse ainsi que leurs utilisations
US20210292299A1 (en) * 2018-06-25 2021-09-23 Dana-Farber Cancer Institute, Inc. Taire family kinase inhibitors and uses thereof

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US20190119289A1 (en) * 2016-04-06 2019-04-25 The Regents Of The University Of Michigan Monofunctional intermediates for ligand-dependent target protein degradation
US20210292299A1 (en) * 2018-06-25 2021-09-23 Dana-Farber Cancer Institute, Inc. Taire family kinase inhibitors and uses thereof
WO2020172655A1 (fr) * 2019-02-23 2020-08-27 New York University Photac photocommutables et leur synthèse ainsi que leurs utilisations

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TOKARSKI II, RJ ET AL.: "Bifunctional degraders of cyclin dependent kinase 9 (CDK9): Probingthe relationship between linker length, properties, and selective protein degradation", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 254, 5 June 2023 (2023-06-05) - 5 April 2023 (2023-04-05), XP093092933, DOI: 10.1016/j.ejmech.2023.115342 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12097261B2 (en) 2021-05-07 2024-09-24 Kymera Therapeutics, Inc. CDK2 degraders and uses thereof
CN117736187A (zh) * 2024-02-19 2024-03-22 天津匠新致成科技有限公司 一种蛋白水解靶向嵌合体及其制备方法、药物组合物和应用
CN117736187B (zh) * 2024-02-19 2024-04-30 天津匠新致成科技有限公司 一种蛋白水解靶向嵌合体及其制备方法、药物组合物和应用

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